The innate immune responses are generally the first line of defense against invading pathogens, but it is controversial whether HBV replicates without activating the innate immunity or actively inhibits the innate pathways in the hepatocytes. To address this question, we used various hepatocyte culture models including hepatoma cell lines expressing viral receptor-NTCP, stem cell-derived hepatocytes and primary human hepatocytes. Using either transfection of HBV genome-containing plasmids or infection by infectious cell culture-generated HBV or patient-derived virus in human hepatoma cell lines and primary or stem cell-derived human hepatocytes, we have established various cell culture models of HBV infection and replication. Despite a robust HBV replication, no interferons (IFNs) or IFN-stimulated genes were induced. Using primary human hepatocyte engrafted SCID/uPA mice, HBV infection was established in vivo. At the peak of viremia, no induction of human IFN could be detected in the liver. These observations indicate a lack of innate immunity in terms of interferon response in HBV infected hepatocytes. To study if HBV actively inhibits innate immune sensing, poly IC and Sendai virus, known to be potent inducers of interferon response, were tested in hepatocyte culture that were infected with HBV. Both type I and III IFNs as well as IFN-stimulated genes were strongly induced by the poly IC or Sendai virus. But concurrent HBV infection did not affect the magnitude nor breadth of this response. Confocal microscopy at single cell level further confirmed that HBV infected hepatocytes exhibited strong nuclear IRF3 and STAT1 expression after Sendai virus infection, similar to that of non-infected cells. Since HCV is known to induce a robust interferon response in infected hepatocytes, we also examined the interferon response in the HBV/ HCV co-infection setting. We co-infected HBV and HCV in primary human hepatocytes and studied their replication and the interferon response. We observed that HBV did not alter HCV replication nor down-regulate the well-known induction of interferon response by HCV, as compared to the HCV mono-infection. HBV infection generates both viral DNA and RNA during propagation, which could be detected by various PRRs. We thus characterized expression and functions of various pattern recognition receptors (PRRs) in different hepatic cell models. We showed that hepatocytes are deficient in DNA sensing machinery, which likely contributes to the lack of IFN response in HBV infected hepatocytes. These findings support the notion that HBV does not actively interfere with the innate sensing mechanism of the hepatocytes. Taken together, our results indicate that HBV behaves like a stealth virus and is not sensed by the innate immunity of the infected hepatocytes, potentially explaining the propensity of HBV to chronic infection. The lack of interplay between HBV infection and hepatocytes innate immunity raises the intriguing question of how HBV eventually activates adaptive immunity of infected host. To partly address this question, we studied the response of macrophages to HBV. We showed that HBV is capable of activating macrophages to produce various cytokines at high viral titers, which may mark the initial step of an HBV-specific immune response, potentially explaining the long window period during acute infection and HBVs propensity to chronic infection. Chronically HBV-infected individuals are at high risk of developing cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms whereby HBV causes HCC are largely unknown. By using a biologically relevant system of HBV infection of primary human hepatocytes (PHHs), we studied how HBV perturbs gene expressions and signaling pathways of infected hepatocytes, and whether these effects are relevant to productive HBV infection and HBV-associated HCC. Using a human growth factor antibody array, we first showed that HBV infection induced a distinct profile of growth factor production by PHHs, marked particularly by significantly lower levels of transforming growth factor (TGF)-beta family of proteins in the supernatant. Transcriptome profiling next revealed multiple changes in cell proliferation and cell cycle control pathways in response to HBV infection. A human cell cycle PCR array validated deregulation of more than 20 gene associated with cell cycle in HBV-infected PHHs. Cell cycle analysis demonstrated that HBV-infected PHHs are enriched in the G2/M phase as compared to the predominantly G0/G1 phase of cultured PHHs. HBV proviral host factors, such as PPARA, RXRA and CEBPB, were up-regulated upon HBV infection and particularly enriched in cells at the G2/M phase. Together, these results support that HBV deregulates cell cycle control to render a cellular environment that is favorable for productive HBV infection. By perturbing cell cycle regulation of infected cells, HBV may coincidently induce a premalignant phenotype that predispose infected hepatocytes to subsequent malignant transformation. Ground glass hepatocyte (GGH) represents a histological hallmark of chronic hepatitis B virus (HBV) infection and is marked by an overabundance of surface antigens (HBsAg) in the endoplasmic reticulum (ER). Stress in the ER can activate unfolded protein response (UPR) pathways. Whether HBV infection or individual HBV proteins can activate UPR remains unknown. Here we aim to investigate the molecular mechanism of how HBV infection induces ER stress and GGH. HepG2-NTCP or primary human hepatocyte (PHH) were transduced with recombinant adenoviral vectors expressing replication-competent HBV genome or individual HBV genes, and high-titer infectious HBV generated in cell culture. Real time qPCRs to quantify ER stress markers including GRP78, ATF4, GADD34 and CHOP were performed. Expression of GRP78 was further determined by Western blotting and immunohistochemistry (IHC). Apoptosis was measured by Caspase3/7 assay and cell viability evaluated by ATPlite assay. GRP78 and HBsAg were visualized by IHC in liver biopsies of chronic hepatitis patients. The UPR markers (GRP78, ATF4, GADD34 and CHOP), were markedly induced by overexpression of HBsAg in HepG2-NTCP cells and PHH. They were not affected by HBV replication or expression of other individual viral proteins with the exception of a modest induction by HBeAg overexpression in PHH. Elevation of UPR genes showed a dose-dependent correlation with increasing HBsAg levels that were only achieved by HBsAg overexpression but not in HBV-infected cells. HBsAg overexpression led to an increased expression of GRP78 that co-localized with HBsAg in HepG2-NTCP cells by confocal microscopy. The increased expression of GRP78 and its co-localization with HBsAg was also confirmed in GGHs of HBV-infected livers. Prolonged activation of UPR by high level of HBsAg induced apoptosis of cells and deregulated cells growth in cell culture. In HBV-infected livers, GGHs showed evidence of UPR and apoptotic features. Over-expression of HBsAg induces ER stress through protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway of UPR in vitro and in vivo and is probably linked to the appearance of GGH in HBV-infected liver. The activation of UPR with resulting apoptosis by HBsAg overexpression observed may lead to cell death and cellular changes of infected hepatocytes associated with a premalignant phenotype.